Aging and age-related diseases, such as osteoarthritis (OA), result in pathological changes to the synovial fluid in joints, reducing lubrication function and leading to degenerative wear and often to pain and disability. Synovial joints are defined by a synovial cavity bathed in lubricating synovial fluid (SF) that is constrained by the joint capsule, a fibrous tissue consisting of a cellular intimal layer, the synovium, and a loose connective sub-intimal layer, the subsynovium. SF is an ultrafiltrate of plasma, filtered through synovium, with additional lubricants secreted by local cell populations. During normal joint articulation, the bulk of the SF shifts within the joint cavity and joint capsule tissue deforms, though little is known about the magnitude of these deformations and their effect on molecular transport. The volumetric and local strain magnitudes of joint capsule have not been determined, though the secretion rates of SF lubricants are known to be mechanosensitive. The transport and secretion characteristics of synovium and cartilage play a large role in determining SF lubricant homeostasis and the ability of SF to provide low-friction, low-wear cartilage-on- cartilage sliding during joint articulation. The biomechanical and transport characteristics of joint capsule tissue are altered in aging and in OA, a debilitating joint disease with a high social and economic burden. Animal models of aging and OA have been described, including aged rodent strains, an intraarticular ribose injection model of advanced glycation end-product (AGE) accumulation in joint tissues with age, and an anterior cruciate ligament transaction (ACLT) surgical destabilization model of OA in rats. Thus, the hypothesis of this proposal is that the mechanical properties of joint capsule and synovium are altered with age and age-related disease, affecting the transport characteristics of macromolecules through the tissue, and contributing to changes in synovial fluid composition in rat models of aging and OA. The proposed experiments will provide the first analysis of joint capsule volumetric and local strains in three rat models of aging and age-related disease. In addition, the transport and secretion rates of lubricant molecules in SF will be assessed, allowing a detailed modeling analysis of lubricant homeostasis and the dysregulation in aging and disease that likely contributes to decreased SF lubrication, cartilage wear, synovium inflammation, and increased lubricant transport and loss, which leads to further decreased SF lubricating ability. A compartmental model of the joint will be extended to allow for theoretical investigation of the effects of disease perturbations on the joint, such as altered lubricant secretion rates. These results may also be useful in identifying potential clinical intervention points and strategies to reverse pathological joint changes due to aging and OA. PUBLIC HEALTH RELEVANCE: Aging and age-related diseases, such as osteoarthritis, result in pathological changes to the synovial fluid in joints, reducing lubrication function and leading to degenerative wear and often to pain and disability. The goals of this project are to better understand and model healthy and pathological synovial fluid lubricant molecule homeostasis by determining joint capsule biomechanics and lubricant molecule transport and secretion rates. The results will improve our understanding of aging and osteoarthritic changes in joints and help identify potential clinical intervention strategies.